The unfolded protein response (UPR) is an intracellular signaling pathway largely controlled by two ER transmembrane kinases?IRE1? and PERK?that communicate the protein folding status of the endoplasmic reticulum (ER) to the nucleus in order to maintain homeostasis within this organelle. Hypoxia, nutrient deprivation, proteasome dysfunction, or sustained demands on the secretory pathway--conditions often encountered by solid tumor cells--lead to the accumulation of misfolded proteins in the ER and cause ?ER stress.? Under remediable levels of ER stress, the UPR activates transcriptional and translational changes that promote adaptation (Homeostatic UPR). But when confronted with irremediable levels of ER stress, these adaptive measures fail, and the UPR instead switches strategies to trigger cell death (Terminal UPR). Neuroendocrine tumors (e.g. carcinoids) are one class of solid tumor that may be particularly sensitive to protein folding stress due to their high protein secretory activity. Derived from professional secretory cells, neuroendocrine tumors can arise in many sites (e.g. gastrointestinal tract, lung), but these tumors universally hypersecrete one or more peptide hormone(s). For the nearly 12,000 Americans diagnosed with a neuroendocrine tumor each year, surgery is the only potentially curative treatment. Unfortunately, the five year survival is extremely low for the ~25% of patients who develop metastatic disease. We have evidence that the UPR is upregulated and required for the growth of pancreatic neuroendocrine tumors (PanNETs), a representative model for this class of secretory solid tumors. Based on our preliminary data, we hypothesize that PanNETs are reliant on elevated levels of Homeostatic UPR signaling to avoid the toxic effects of protein folding stress, and that targeted interventions to either reduce Homeostatic UPR outputs or alternatively trigger the Terminal UPR will have potent antitumor effects. We will use a variety of genetic, chemical-genetic, and pharmacological tools developed in our laboratory to selectively activate or disable the UPR master regulators (IRE1? and PERK) in order to accomplish two specific aims. (1): Define the activation status, signaling outputs, and cell growth effects of the UPR regulators IRE1? and PERK in primary human samples and murine xenograft models of PanNETs. (2): Determine the effects of pharmacologic inhibition of IRE1? and/or PERK on the growth of PanNETs in murine xenograft and genetic models of PanNETs. Our research project will provide powerful mechanistic insights into the role of the UPR on PanNET growth and the use of small molecules to manipulate this pathway to control cell fate. If successful, our work promises to validate drug targets to modify progression of PanNET and other neuroendocrine tumors.